The present invention provides poly-toll like receptor antagonist (TLR). The tolls like receptors (TLR) are family of proteins. The innate immune system recognizes pathogens and initiates an effective and appropriate response through TLRs. TLRs are part of the larger IL-IR/TLR super family, which includes IL-IRs, IL-18Rs, and a group of orphan receptors. The family is defined by the presence of a cytoplasmic Toll-like-IL-1 resistance (TIR) domain, which is responsible for mediating downstream signaling. So far, 13 TLRs have been identified; TLRs 1-9 are common to mouse and human, whereas TLR10 is only functional in humans, and TLRs 11, 12, and 13 have been found only in mice. Many but not all of these receptors have been assigned a role in the initial detection of, and response to, specific pathogen-associated molecules (PAMs).
In macrophages and neutrophils, this drives innate immune responses, such as inflammation and induction of microbicidal activity, whereas activation of TLRs expressed on dendritic cells leads to the initiation of adaptive immunity through induction of IL-12 and co-stimulatory molecules.
Though TLRs are part of protective system of the body, their over expression is associated with variety of diseases. Sepsis is one of such disease. The incidence of sepsis due to infection in the United States has been estimated to be approximately 750,000 cases per year, with a mean mortality rate of about 30% (Angus et al., Crit. Care Med. Vol. 29, (2001), p 1303-1310). Endotoxin, or lipo-polysaccharide (LPS), which is a major component of the cell wall of gram-negative bacteria, is the causative agent of gram-negative sepsis. Endotoxin induces an innate immune response mainly through toll-like receptor 4 (TLR4) (Medzhitov et al., Nature Vol. 388(6640), (1997), p 394-397) in infected hosts, by which the body is warned of the bacterial infection, thus leading to an antimicrobial attack by the host immune system. Such an immune response is usually beneficial to infected hosts, however, an overwhelming immune response to endotoxin can be pathological, leading to systemic inflammatory response syndrome (SIRS), organ failure, several sepsis and, possibly, septic shock and death. The symptoms of these conditions include fever, generalized inflammation, and more severe conditions, such as disseminated intravascular coagulation (DIC), hypotension, acute renal failure, acute respiratory distress syndrome (ARDS), hepatocellular destruction, and cardiac failure.
Toll like receptors expressed by LPS include TLR 2, 9, others besides TLR4. While endotoxin itself is a highly heterogeneous molecule, the expression of many of the toxic properties of endotoxin is attributed to the highly conserved hydrophobic lipid A portion. An effective drug that acts as a TLR4 antagonist, and which is an antagonist to this conserved structure of Lipid A, is known as E5564 (also known as compound 1287, SGEA, and Eriforan) (Mullarkey et al., J. Pharmacol. Exp. Ther. 304 (3): 1093-1102, 2003). This drug is described as compound 1 in U.S. Pat. No. 5,681,824, WO/2004/071465 (Methods and kits for use in the diagnosis and treatment of endotoxemia) describes A method of determining whether a patient could benefit or continue to benefit from treatment with a toll-like receptor 4 (TLR4) antagonist. It is also known that inhibition of Toll-like receptor 4 with eritoran attenuates myocardial ischemia-reperfusion injury. Circulation 114(1 Suppl), (2006), p 1270-4
The other diseases wherein one or more TLRs are over expressed include but not limited to following,                1. Exacerbation of latent or active viral infections (e.g., infection with HIV, cytomegaloviruses, herpes simplex, and influenza virus),        2. Inborn or acquired predisposition to pulmonary bacterial infection,        3. Congestive heart failure with pulmonary edema.        4. Chronic obstructive pulmonary disease        5. multiple myeloma        6. SLE.        7. Lupus        8. Ulcerative colitis        9. Crohn's disease        10. Autoimmune diseases        11. Rheumatoid diseases        12. Chronic hepatitis        13. Malaria (P. Falciparum)        14. Multiple sclerosis        15. Optic neuritis.        16. Viral encephalitis (West Nile)        17. Candidiasis        18. Atherosclerosis        
Some of these disorders are amenable to conventional therapy while there is no definitive therapy for majority of the diseases.
Selected antibacterial, anti-inflammatory, and immunomodulating adjunctive therapies investigated in patients with severe sepsis and septic shock.
Type of therapyTarget (s)AgentsNeutralisation of microbialEndotoxinAnti-endotoxin antibodies,toxinsanti-lipid A antibodies,lipopolysaccharideanalogues,lipopolysaccharide removalNon-specificMultiple inflammatory andHigh dose corticosteroids,anti-inflammatory andimmune mediatorslow dose corticosteroids,immunomodulating drugspentoxifylline,immunoglobulins, interferongammaInhibition of specificPro-inflammatoryAnti-tumour necrosis factorMediatorscytokines: Tumour necrosisantibodies, soluble tumourFactornecrosis factor receptorsInterleukin-1 PhospholipidInterleukin-1 receptorcomponents:antagonistPhospholipase A2Phospholipase A2 inhibitorCyclo-oxygenaseIbuprofenThromboxaneDazoxiben, ketoconazolePlatelet activating factorPlatelet activating factorantagonists platelet activatingfactor acetylhydrolaseOxygen free radicalsN-acetylcysteine, seleniumNitric oxideN-methyl-L-arginineBradykininBradykinin antagonistCorrection of CoagulationAntithrombin III, tissueactivated protein Ccascade coagulopathyfactor pathway inhibitor,
In spite of all these morbidity associated with sepsis has not reduced. Thus there is a need to provide better therapeutic options for such diseases.
Mycobacterium w is a non-pathogenic, cultivable, atypical mycobacterium, with biochemical properties and fast growth characteristics resembling those belonging to Runyons group IV class of Mycobacteria. It has been found to share antigens with Mycobacterium leprae and Mycobacterium tuberculosis. It is found to provide prophylaxis against leprosy in humans by converting lepromin negative individuals to lepromin positivity. It is also found to provide prophylaxis against tuberculosis in animals. In leprosy it is also found to reduce duration of therapy for bacterial killing, clearance as well as clinical cure when used along with multi drug therapy. The pharmaceutical composition containing Mycobacterium W is approved for human use since 1998 in India.
This has been described in various patents and publications. Heat killed mycobacterium w is available as a commercial preparation in India. It contain 0.5×109 cells heat killed of Mycobacterium W per 0.1 ml of pharmaceutical composition.